My immediate career goals are to obtain the credentials and funding necessary to achieve independence as an investigator. My long term career goals are to provide insights into the mechanisms of diabetes and its cardiovascular complications. In particular, my objective is to answer several major questions regarding this subject within the context of a 20-30 year scientific career. My research career development plan is to acquire expertise in a variety of experimental techniques, molecular biological concepts, and administrative skills via coursework, bench training, seminars/conferences, and feedback from a specially-created Advisory Committee of senior investigators within my department. Project description: Insulin resistance (IR) is a pathophysiologic hallmark of type 2 diabetes, and the metabolic syndrome. Despite considerable impact on public health, its mechanistic basis remains largely uncertain. Of late, increased attention has been focused on the role of adipocytes in the pathogenesis of IR. In particular, adipocytes produce and secrete several peptides, cytokines, and other substances collectively known as "adipokines." Several adipokines are known to modulate insulin sensitivity, and as such are thought to be key players in the development of IR. The 36 amino acid peptide apelin is a novel bioactive molecule that possesses numerous tissue-specific actions in various organs, including the heart, brain, and gut. In addition, apelin is secreted by adipocytes, and is thus considered an adipokine. Unfortunately, very little is known about the biology of apelin as it pertains to adipocytes. Given the importance of adipokines as regulators of insulin sensitivity, apelin may also be similarly involved in IR. The Specific Aims attempt to address this issue by ascertaining the regulation and downstream effects of adipocyte-derived apelin. (1) To elucidate the role of HIF-1 in the regulation of apelin in adipocytes. (2) To determine the modulatory effects of apelin on insulin sensitivity. (3) To assess the effect of adipocyte-produced apelin on the heart. RELEVANCE: Apelin is a recently discovered hormone that has made by fat tissue. Apelin is suspected to be involved in the development of insulin resistance, which is a highly prevalent and morbid condition thought to be the major factor underlying type 2 diabetes. Elucidating apelin's role in insulin resistance may lead to novel therapeutic strategies to address this common and consequential public health problem.